The genetic factors underlying resistance to growth of AKR lymphoma cells have been investigated. An F1 hybrid (AKD2 F1) of AKR/J mice, as well as H-2 compatible (AKR/Cu, CBA) mice show prolonged or indefinite survival following injection of AKR/J lymphoma cells. This in vivo resistance correlates with in vitro assays of cell-mediated cytotoxicity (CMC). Resistance of AKDF1 mice is dose dependent, and not absolute; eventually, these mice succumb to leukemia. The AKR/Cu mice, which are known to differ from the AKR/J lymphoma donors only at the 9th chromosome, show more profound resistance at doses of less than 10 to the 6th power AKR/J lymphoma cells. The AKR/Cu mutant does not have any detectable tumor growth. CBA/J mice, which are also H-2 compatible, show complete resistance to even greater doses of AKR/J lymphoma. The F1 in vitro CMC can be elicited as a weak primary response, detectable at effector: target ratios of ca:80/1 on tumor targets. In contrast, the AKR/Cu alpha AKR/J or CBA alpha AKR/J CMC is detectable only after in vivo priming. However, the secondary response in vitro is almost as strong as a primary allogeneic response. The only known antigenic difference between AKR/Cu and AKR/J mice is the Thy antigen. Both strains are high Gross virus producers and have a high spontaneous incidence of T-cell lymphoma. The basis of this strong resistance to the reciprocal strain tumor is of some interest. AKR/Cu and AKR/J mice will be challenged with the reciprocal lymphoma cells and observed for long-term survival. It will be of considerable interest to determine whether by priming against the reciprocal strain, one can prevent or reduce the strains' own high spontaneous incidence of lymphoma.